PROJECT SUMMARY/ABSTRACT Children with benign epilepsy with centrotemporal spikes (BECTS), the most common pediatric epilepsy syndrome, have a mild seizure disorder but have moderate language difficulties, the pathophysiology of which is currently unknown. Many posit that interictal epileptiform discharges (IEDs) arising from one or both motor cortices disrupt language development, possibly by driving atypical connectivity between the motor and language networks. Supporting this, the candidate found that response of the motor cortex to transcranial magnetic stimulation (TMS) specifically correlates with performance on a language learning task in BECTS subjects. The aim of the proposed studies is to use a combination of high-density EEG (HD-EEG) alone and HD-EEG paired with TMS (TMS-EEG) to determine if IEDs disrupt language function by altering brain connectivity. The central hypothesis is that IEDs pathologically strengthen connectivity between the motor and language regions, thus inhibiting development of efficient connectivity within the language network. Aim 1 will define the immediate impact of IEDs on connectivity between the motor and language regions. Aim 2 will determine if children with BECTS have decreased connectivity within the language network compared to controls and whether disrupted connectivity predicts language dysfunction. We do not typically treat IEDs in BECTS as medications have limited efficacy and global neurologic impact. In contrast, repetitive trains of TMS (rTMS) have therapeutic potential for the treatment of IEDs as rTMS induces focal changes in cortical excitability. Thus, Aim 3 will determine if rTMS to the motor cortex reduces IED frequency and normalizes connectivity in children with BECTS. Dr. Baumer is a pediatric epileptologist at Stanford University who is establishing herself as an investigator in patient-oriented research. Her goal is to advance our mechanistic understanding of cognitive comorbidities in pediatric epilepsy. Dr. Baumer?s clinical training coupled with her background in TMS and clinical research make her ideally suited to contribute in this area. The training plan outlined in this application will allow Dr. Baumer to develop expertise in: (1) the conceptual and practical analysis of HD-EEG and TMS-EEG data with emphasis on connectivity analysis; (2) the design and implementation of pediatric TMS-EEG studies; and (3) the neurodevelopment and assessment of language processing. To achieve these goals, she has assembled a mentorship team of internationally recognized physician-scientists with expertise in the measurement and modulation of brain connectivity as well as the neuroscience of language development. She has recruited advisors with methodologic expertise in pediatric TMS, HD-EEG, and epilepsy research. Along with her mentors, Dr. Baumer has chosen laboratory rotations and courses that complement her research to ensure that she reaches her training goals. Upon conclusion of the award, Dr. Baumer will be optimally positioned to lead a pediatric neurostimulation research program that focuses on the interactions of epilepsy and cognition.